A Mouse Model for Intellectual Disability Caused by Mutations in the X-Linked 2′‑O‑Methyltransferase Ftsj1 Gene
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Accepted Manuscript A mouse model for intellectual disability caused by mutations in the X-linked 2′'O'methyltransferase Ftsj1 gene Lars R. Jensen, Lillian Garrett, Sabine M. Hölter, Birgit Rathkolb, Ildikó Rácz, Thure Adler, Cornelia Prehn, Wolfgang Hans, Jan Rozman, Lore Becker, Juan Antonio Aguilar-Pimentel, Oliver Puk, Kristin Moreth, Monika Dopatka, Diego J. Walther, Viola von Bohlen und Halbach, Matthias Rath, Martin Delatycki, Bettina Bert, Heidrun Fink, Katharina Blümlein, Markus Ralser, Anke Van Dijck, Frank Kooy, Zornitza Stark, Sabine Müller, Harry Scherthan, Jozef Gecz, Wolfgang Wurst, Eckhard Wolf, Andreas Zimmer, Martin Klingenspor, Jochen Graw, Thomas Klopstock, Dirk Busch, Jerzy Adamski, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabě de Angelis, Oliver von Bohlen und Halbach, Hans-Hilger Ropers, Andreas W. Kuss PII: S0925-4439(18)30497-6 DOI: https://doi.org/10.1016/j.bbadis.2018.12.011 Reference: BBADIS 65360 To appear in: BBA - Molecular Basis of Disease Received date: 6 July 2018 Revised date: 6 December 2018 Accepted date: 10 December 2018 Please cite this article as: Lars R. Jensen, Lillian Garrett, Sabine M. Hölter, Birgit Rathkolb, Ildikó Rácz, Thure Adler, Cornelia Prehn, Wolfgang Hans, Jan Rozman, Lore Becker, Juan Antonio Aguilar-Pimentel, Oliver Puk, Kristin Moreth, Monika Dopatka, Diego J. Walther, Viola von Bohlen und Halbach, Matthias Rath, Martin Delatycki, Bettina Bert, Heidrun Fink, Katharina Blümlein, Markus Ralser, Anke Van Dijck, Frank Kooy, Zornitza Stark, Sabine Müller, Harry Scherthan, Jozef Gecz, Wolfgang Wurst, Eckhard Wolf, Andreas Zimmer, Martin Klingenspor, Jochen Graw, Thomas Klopstock, Dirk Busch, Jerzy Adamski, Helmut Fuchs, Valérie Gailus-Durner, Martin Hrabě de Angelis, Oliver von Bohlen und Halbach, Hans-Hilger Ropers, Andreas W. Kuss , A mouse model for intellectual disability caused by mutations in the X-linked 2′'O'methyltransferase Ftsj1 gene. Bbadis (2018), https://doi.org/10.1016/ j.bbadis.2018.12.011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT A mouse model for intellectual disability caused by mutations in the X-linked 2’-O-methyltransferase Ftsj1 gene. Lars R. Jensen1,*, Lillian Garrett2,3, Sabine M. Hölter2,3, Birgit Rathkolb2,4,5, Ildikó Rácz2,6,7 Thure Adler2, Cornelia Prehn2, Wolfgang Hans2, Jan Rozman2,5, Lore Becker2, Juan Antonio Aguilar-Pimentel2, Oliver Puk3, Kristin Moreth2, Monika Dopatka8, Diego J. Walther9, Viola von Bohlen und Halbach10, Matthias Rath11, Martin Delatycki12, Bettina Bert13, Heidrun Fink13, Katharina Blümlein14, Markus Ralser15, Anke Van Dijck16,17, Frank Kooy16, Zornitza Stark12, Sabine Müller18, Harry Scherthan19, Jozef Gecz20, Wolfgang Wurst3,21,22,23, Eckhard Wolf4, Andreas Zimmer6, Martin Klingenspor24,25, Jochen Graw3, Thomas Klopstock22,23,26 Dirk Busch27, Jerzy Adamski2,28, Helmut Fuchs2, Valérie Gailus-Durner2, Martin Hrabě de Angelis2,5,28,Oliver von Bohlen und Halbach10, Hans-Hilger Ropers9, Andreas W. Kuss1,* 1Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Strasse 8, 17489 Greifswald, Germany 2German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany 3Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany 4Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig- Maximilians-University München, Feodor-Lynen Str. 25, 81377 München, Germany 5German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany 6Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Sigmund Freud Str. 25, 53127 Bonn, Germany 7Clinic of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn Medical Center, Bonn, Germany 8Depertment of ExperimentalACCEPTED Neurology, Charite, MANUSCRIPT Berlin, Germany 9Max Planck Institute for Molecular Genetics, Berlin, Germany. 10Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany 11Department of Human Genetics, University Medicine Greifswald and Interfaculty Institute of Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany 12Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Victoria, Australia 13Institute for Pharmacology and Toxicology, FB Veterinary Medicine, Free University, Berlin, Germany 1 ACCEPTED MANUSCRIPT 14Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany 15Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK 16University of Antwerp, Department of Neurology - Antwerp University Hospital, Edegem, Belgium 17Department of Medical Genetics, University of Antwerp, Antwerp, Belgium 18Institute of Biochemistry, University Greifswald, Greifswald, Germany. 19Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Munich, Germany 20School of Medicine, and the Robinson Research Institute, the University of Adelaide, and South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia. 21Chair of Developmental Genetics, Technische Universität München, Freising- Weihenstephan, Germany 22Deutsches Institut für Neurodegenerative Erkrankungen (DZNE), Site Munich, 80336 München, Germany 23Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig- Maximilians-Universität München, Schillerstr. 44, 80336 München 24Chair of Molecular Nutritional Medicine, Technical University Munich, EKFZ – Else Kröner Fresenius Center for Nutritional Medicine, Gregor-Mendel-Str. 2, 85350 Freising- Weihenstephan, Germany 25ZIEL – Institute for Food and Health, Technical University Munich, Gregor-Mendel-Str. 2, 85350 Freising-Weihenstephan, Germany 26Department of Neurology, Friedrich-Baur-Institute, Klinikum der Ludwig-Maximilians- Universität München, Ziemssenstr. 1a, 80336 München, Germany 27Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Trogerstrasse 30, 81675 Munich, Germany 28 Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Alte Akademie 8, 85354 Freising, Germany *Corresponding authors ACCEPTED MANUSCRIPT Abstract Mutations in the X chromosomal tRNA 2’-O-methyltransferase FTSJ1 cause intellectual disability (ID). Although the gene is ubiquitously expressed affected individuals present no consistent clinical features beyond ID. In order to study the pathological mechanism involved in the aetiology of FTSJ1 deficiency-related cognitive impairment, we generated and characterized an Ftsj1 deficient mouse line based on the gene trapped stem cell line RRD143. Apart from an impaired learning capacity these mice presented with several statistically significantly altered features related to behaviour, pain sensing, bone and energy 2 ACCEPTED MANUSCRIPT metabolism, the immune and the hormone system as well as gene expression. These findings show that Ftsj1 deficiency in mammals is not phenotypically restricted to the brain but affects various organ systems. Re-examination of ID patients with FTSJ1 mutations from two previously reported families showed that several features observed in the mouse model were recapitulated in some of the patients. Though the clinical spectrum related to Ftsj1 deficiency in mouse and man is variable, we suggest that an increased pain threshold may be more common in patients with FTSJ1 deficiency. Our findings demonstrate novel roles for Ftsj1 in maintaining proper cellular and tissue functions in a mammalian organism. Keywords Ftsj1, tRNA methyltransferase, intellectual disability, X-linked, mouse model 1. Introduction Intellectual disability (ID) is defined by significant limitations in intellectual performance (intelligence quotient <70) and a reduction of conceptual, social and practical skills with an onset before the age of 18. ID is a major developmental disorder and currently ID is estimated to affect around 1% of the general population, but with large regional differences (1). Historically ID was separated into syndromic and non-syndromic forms, with the former being ID in the presence of clinically consistent features. The non-syndromic forms seem more common, but as more patients with similar gene defects are molecularly diagnosed syndromic features may become apparent. Although ID has genetic as well as environmental causes (like excessive alcohol consumption during pregnancy), severe forms are often caused by genetic defects in single genes (2–4). Monogenic recessive causes of ID have been excessively studied in X-linked forms and with the development of next-generation-sequencing techniques the elucidation of autosomal forms has also made a leap forward. Mutation discovery studies so far have clearly shown that ID is genetically and functionally heterogeneous but also that several ID proteins interact, are involvedACCEPTED in the same process or MANUSCRIPTtarget the same substrate.